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  • 1.
    Aarnio, Mikko
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Fredriksson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Wolf, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Peterson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Linnman, Clas
    Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol, Boston, MA USA.
    Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.2017Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, nr 1, s. 418-424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

  • 2.
    Backryd, Emmanuel
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Pain & Rehabil Ctr, Linkoping, Sweden..
    Tanum, Lars
    Akershus Univ Hosp, Dept R&D Mental Hlth, Lorenskog, Norway..
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma2017Ingår i: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In addition to central hyperexcitability and impaired top-down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n= 10) and plasma from blood donor controls (n= 46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

  • 3. Basnet, A.
    et al.
    Butler, Stephen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Honore, P. H.
    Butler, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Gordh, Torsten E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Kristensen, K.
    Bjerrum, O. J.
    Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study2014Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 58, nr 1, s. 61-73Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundThe first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. MethodsThe clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400mg daily, and (2) addition of donepezil 5mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. ResultsEight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (>11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P<0.0001 combination vs. monotherapy). ConclusionDonepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.

  • 4.
    Bothelius, Kristoffer
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Kyhle, Kicki
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Broman, Jan-Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Initial Sleep Time Predicts Success in Manual-Guided Cognitive Behavioral Therapy for Insomnia2016Ingår i: Behavioural Sleep Medicine, ISSN 1540-2002, E-ISSN 1540-2010, Vol. 14, nr 4, s. 378-388Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cognitive behavioral therapy produces significant and long-lasting improvement for individuals with insomnia, but treatment resources are scarce. A "stepped care" approach has therefore been proposed, but knowledge is limited on how to best allocate patients to different treatment steps. In this study, 66 primary-care patients with insomnia attended a low-end treatment step: manual-guided cognitive behavioral therapy (CBT) for insomnia delivered by ordinary primary-care personnel. Based on clinically significant treatment effects, subjects were grouped into treatment responders or nonresponders. Baseline data were analyzed to identify predictors for treatment success. Long total sleep time at baseline assessment was the only statistically significant predictor for becoming a responder, and sleep time may thus be important to consider before enrolling patients in low-end treatments.

  • 5.
    Buhrman, Monica
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Fredriksson, Anders
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Edström, G.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Shafiei, D.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Tärnqvist, C.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Ljóttson, B.
    Hursti, Timo
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Andersson, G.
    Guided Internet-delivered cognitive behavioural therapy for chronic pain patients who have residual symptoms after rehabilitation: Randomized controlled trial2013Ingår i: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 17, nr 5, s. 753-765Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Chronic pain can be treated with cognitive behavioural therapy delivered in multidisciplinary settings. However, relapse is likely, and there is a need for cost-effective secondary interventions for persons with residual problems after rehabilitation. The aim of the present study was to investigate the effects of a guided Internet-delivered cognitive behavioural intervention for patients who had completed multidisciplinary treatment at a pain management unit. Methods A total of 72 persons with residual pain problems were included in the study and were randomized to either treatment for 8 weeks or to a control group who were invited to participate in a moderated online discussion forum. The participants had different chronic pain conditions, and a majority were women (72%). Twenty-two percent of the participants dropped out of the study before the post-treatment assessment. Results Intent-to-treat analyses demonstrated differences on the catastrophizing subscale of the Coping Strategies Questionnaire (Cohen's d=0.70), in favour of the treatment group but a small within-group effect. Differences were also found on other measures of pain-related distress, anxiety and depressive symptoms. A 6-month follow-up exhibited maintenance of improvements. Conclusions We conclude that Internet-delivered treatment can be partly effective for persons with residual problems after completed pain rehabilitation.

  • 6.
    Buhrman, Monica
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Andersson, Gerhard
    Internet interventions for chronic pain including headache: A systematic review2016Ingår i: Internet Interventions, ISSN 2214-7829, Vol. 4, s. 17-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic pain is a major health problem and behavioral based treatments have been shown to be effective. However, the availability of these kinds of treatments is scarce and internet-based treatments have been shown to be promising in this area. The objective of the present systematic review is to evaluate internet-based interventions for persons with chronic pain. The specific aims are to do an updated review with a broad inclusion of different chronic pain diagnoses and to assess disability and pain and also measures of catastrophizing, depression and anxiety. A systematic search identified 891 studies and 22 trials were selected as eligible for review. Two of the selected trials included children/youth and five included individuals with chronic headache and/or migraine. The most frequently measured domain reflected in the primary outcomes was interference/disability, followed by catastrophizing. Result across the studies showed a number of beneficial effects. Twelve trials reported significant effects on disability/interference outcomes and pain intensity. Positive effects were also found on psychological variable such as catastrophizing, depression and anxiety. Several studies (n = 12) were assessed to have an unclear level of risk bias. The attrition levels ranged from 4% to 54% where the headache trials had the highest drop-out levels. However, findings suggest that internet-based treatments based on cognitive behavioural therapy (CBT) are efficacious measured with different outcome variables. Results are in line with trials in clinical settings. Meta-analytic statistics were calculated for interference/disability, pain intensity, catastrophizing and mood ratings. Results showed that the effect size for interference/disability was Hedge's g = − 0.39, for pain intensity Hedge's g = − 0.33, for catastrophizing Hedge's g = − 0.49 and for mood variables (depression) Hedge's g = − 0.26.

  • 7.
    Buhrman, Monica
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Skoglund, Astrid
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Husell, Josefin
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Bergström, Kristina
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Hursti, Timo
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Bendelin, Nina
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Andersson, Gerhard
    Guided Internet-delivered acceptance and commitment therapy for chronic pain patients: a randomized controlled trial2013Ingår i: Behaviour Research and Therapy, ISSN 0005-7967, E-ISSN 1873-622X, Vol. 51, nr 6, s. 307-315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acceptance and commitment therapy (ACT) interventions for persons with chronic pain have recently received empirical support. ACT focuses on reducing the disabling influences of pain through targeting ineffective control strategies and teaches people to stay in contact with unpleasant emotions, sensations, and thoughts. The aim of the present study was to investigate the effect of a guided internet-delivered ACT intervention for persons with chronic pain. A total of 76 patients with chronic pain were included in the study and randomized to either treatment for 7 weeks or to a control group that participated in a moderated online discussion forum. Intent-to-treat analyses showed significant increases regarding activity engagement and pain willingness. Measurements were provided with the primary outcome variable Chronic Pain Acceptance Questionnaire which was in favour of the treatment group. Reductions were found on other measures of pain-related distress, anxiety and depressive symptoms. A six month follow-up showed maintenance of improvements. We conclude that an acceptance based internet-delivered treatment can be effective for persons with chronic pain.

  • 8.
    Buhrman, Monica
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Syk, Martin
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Burvall, Olle
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Hartig, Terry
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Andersson, Gerhard
    Individualized Guided Internet-delivered Cognitive Behaviour Therapy for Chronic Pain Patients with Comorbid Depression and Anxiety: A Randomized Controlled Trial2015Ingår i: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 31, nr 6, s. 504-516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Depression and anxiety are commonly seen in patients with chronic pain which affects the patient´s daily life functioning. Although considerable attention has been devoted to explain why depression and anxiety are frequent comorbid with chronic pain, little empirical work has been conducted on interventions that target depression and anxiety and chronic pain. The present study was designed to test an individualized cognitive-behavioral treatment delivered through the internet for persons with chronic pain and emotional distress. A total of 52 patients with chronic pain and depression were included and randomized to either treatment for 8 weeks or to a control group that participated in a moderated online discussion forum. Intent-to-treat analyses showed significant decreases regarding depressive symptoms and pain disability in the treatment group. Results on the primary outcomes of depression and anxiety were in favour of the treatment group. Reductions were also found on pain catastrophizing. One year follow-up showed maintenance of improvements. We conclude that an individualized guided internet-delivered treatment based on cognitive behaviour therapy can be effective for persons with chronic pain comorbid emotional distress.

  • 9.
    Buratovic, Sonja
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Sundell-Bergman, S.
    Swedish Univ Agr Sci, Dept Soil & Environm, Umea, Sweden.
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice2018Ingår i: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 120, nr 3, s. 546-554Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Radiological methods for screening, diagnostics and therapy are frequently used in healthcare. In infants and children, anaesthesia/sedation is often used in these situations to relieve the patients' perception of stress or pain. Both ionising radiation (IR) and ketamine have been shown to induce developmental neurotoxic effects and this study aimed to identify the combined effects of these in a murine model. Methods: Male mice were exposed to a single dose of ketamine (7.5 mg kg(-1) body weight) s.c. on postnatal day 10. One hour after ketamine exposure, mice were whole body irradiated with 50-200 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2, 4 and 5 months of age. At 6 months of age, cerebral cortex and hippocampus tissue were analysed for neuroprotein levels. Results: Animals co-exposed to IR and ketamine displayed significant (P <= 0.01) lack of habituation in the spontaneous behaviour test, when compared with controls and single agent exposed mice. In the Morris Water Maze test, co-exposed animals showed significant (P <= 0.05) impaired learning and memory capacity in both the spatial acquisition task and the relearning test compared with controls and single agent exposed mice. Furthermore, in co-exposed mice a significantly (P <= 0.05) elevated level of tau protein in cerebral cortex was observed. Single agent exposure did not cause any significant effects on the investigated endpoints. Conclusion: Co-exposure to IR and ketamine can aggravate developmental neurotoxic effects at doses where the single agent exposure does not impact on the measured variables. These findings show that estimation of risk after paediatric low-dose IR exposure, based upon radiation dose alone, may underestimate the consequences for this vulnerable population.

  • 10.
    Buratovic, Sonja
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sundell-Bergman, Synnöve
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Ketamine interacts with low dose ionizing radiaiton during brain development to impair cognitive function in mouse2016Ingår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175Artikel i tidskrift (Refereegranskat)
  • 11. Bäckryd, Emmanuel
    et al.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Gerdle, Björn
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls2017Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, nr 12, s. 2487-2495Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

  • 12. Dominguez, Cecilia A.
    et al.
    Kalliomaki, Maija
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Gunnarsson, Ulf
    Moen, Aurora
    Sandblom, Gabriel
    Kockum, Ingrid
    Lavant, Ewa
    Olsson, Tomas
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Rygh, Lars Jorgen
    Roe, Cecilie
    Gjerstad, Johannes
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Piehl, Fredrik
    The DQB1*03:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation2013Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, nr 3, s. 427-433Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n = 189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB1*04 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB1*03:02 allele together with DRB1*04 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n = 258), where carriers of the DQB1*03:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB1*04 - DQB1*03:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms.

  • 13.
    Emami Khoonsari, Payam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Musunri, Sravani
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Herman, Stephanie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden..
    Tanum, Lars
    Department of R&D in Mental Health, Akershus University Hospital, Lørenskog, Norway..
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients2019Ingår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, s. 35-43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling.

  • 14.
    Feresiadou, Amalia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Landtblom: Neurologi.
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Press, Rayomand
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Kmezic, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Nygren, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden..
    Niemelä, Valter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Cunningham, Janet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Burman, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease2019Ingår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, s. 31-36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

    METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

    RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

    CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

  • 15.
    Fredriksson, Anders
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap. Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Archer, Trevor
    Alm, Henrik
    Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Gordh, Torsten
    Institutionen för kirurgiska vetenskaper. Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Eriksson, Per
    Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. Avd för ekotoxikologi.
    Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration.2004Ingår i: Behav Brain Res, ISSN 0166-4328, Vol. 153, nr 2, s. 367-76Artikel i tidskrift (Refereegranskat)
  • 16.
    Fredriksson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset.
    Pontén, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi.
    Neonatal exposure to a combination of N-Methyl-D-aspartate and γ-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits2007Ingår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 107, nr 3, s. 427-436Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: During the brain growth spurt, the brain develops and modifies rapidly. In rodents this period is neonatal, spanning the first weeks of life, whereas in humans it begins during the third trimester and continues 2 yr. This study examined whether different anesthetic agents, alone and in combination, administered to neonate mice, can trigger apoptosis and whether behavioral deficits occur later in adulthood.

    Methods: Ten-day-old mice were injected subcutaneously with ketamine (25 mg/kg), thiopental (5 mg/kg or 25 mg/kg), propofol (10 mg/kg or 60 mg/kg), a combination of ketamine (25 mg/kg) and thiopental (5 mg/kg), a combination of ketamine (25 mg/kg) and propofol (10 mg/kg), or control (saline). Fluoro-Jade staining revealed neurodegeneration 24 h after treatment. The behavioral tests-spontaneous behavior, radial arm maze, and elevated plus maze (before and after anxiolytic)-were conducted on mice aged 55-70 days.

    Results: Coadministration of ketamine plus propofol or ketamine plus thiopental or a high dose of propofol alone significantly triggered apoptosis. Mice exposed to a combination of anesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice that were neonatally exposed to propofol.

    Conclusion: This study shows that both a γ-aminobutyric acid type A agonist (thiopental or propofol) and an N-methyl-d-aspartate antagonist (ketamine) during a critical stage of brain development potentiated neonatal brain cell death and resulted in functional deficits in adulthood. The use of thiopental, propofol, and ketamine individually elicited no or only minor changes.

  • 17.
    Gaetan, Philippot
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Fredriksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Short-term exposure and long-term consequences of neonatal exposure to Δ9-tetrahydrocannabinol (THC) and ibuprofen in mice2016Ingår i: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 307, s. 137-144Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Both Δ9-tetrahydrocannabinol (THC) and ibuprofen have analgesic properties by interacting with the cannabinoid receptor type 1 (CB1R) and the cyclooxygenase (COX) systems, respectively. Evaluation of these analgesics is important not only clinically, since they are commonly used during pregnancy and lactation, but also to compare them with acetaminophen, with a known interaction with both CB1R and the COX systems. Short-term exposure of neonatal rodents to acetaminophen during the first weeks of postnatal life, which is comparable with a period from the third trimester of pregnancy to the first years of postnatal life in humans, induces long-term behavioral disturbances. This period, called the brain growth spurt (BGS) and is characterized by series of rapid and fundamental changes and increased vulnerability, peaks around postnatal day (PND) 10 in mice. We therefore exposed male NMRI mice to either THC or ibuprofen on PND 10. At 2 months of age, the mice were subjected to a spontaneous behavior test, consisting of a 60 min recording of the variables locomotion, rearing and total activity. Mice exposed to THC, but not ibuprofen, exhibited altered adult spontaneous behavior and habituation capability in a dose-dependent manner. This highlights the potency of THC as a developmental neurotoxicant, since a single neonatal dose of THC was enough to affect adult cognitive function. The lack of effect from ibuprofen also indicates that the previously seen developmental neurotoxicity of acetaminophen is non-COX-mediated. These results might be of importance in future research as well as in the ongoing risk/benefit assessment of THC.

  • 18.
    Gerdle, Björn
    et al.
    Linkoping Univ, Pain & Rehabil Ctr, SE-58183 Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Ghafouri, Bijar
    Linkoping Univ, Pain & Rehabil Ctr, SE-58183 Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Ghafouri, Nazdar
    Linkoping Univ, Pain & Rehabil Ctr, SE-58183 Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Backryd, Emmanuel
    Linkoping Univ, Pain & Rehabil Ctr, SE-58183 Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Signs of ongoing inflammation in female patients with chronic widespread pain A multivariate, explorative, cross-sectional study of blood samples2017Ingår i: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 96, nr 9, artikel-id e6130Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This cross-sectional study investigates the plasma inflammatory profile of chronic widespread pain CWP) patients compared to healthy controls CON). Rather than analyzing a relatively few substances at a time, we used a new multiplex proximity extension assay PEA) panel that enabled the simultaneous analysis of 92 inflammation-related proteins, mainly cytokines and chemokines. Seventeen women with CWP and 21 female CON participated and a venous blood sample was drawn from all subjects. Pain intensity and pain thresholds for pressure, heat, and cold were registered. A PEA panel 92 proteins) was used to analyze the blood samples. Multivariate data analysis by projection was used in the statistical analyses. Eleven proteins significantly differentiated the CON and CWP subjects R-2=0.58, Q(2)=0.37, analysis of variance of cross-validated predictive residuals P=0.006). It was not possible to significantly regress pain thresholds within each group CON or CWP). Positive significant correlations existed between several proteins and pain intensities in CWP, but the model reliability of the regression was poor. CWP was associated with systemic low-grade inflammation. Larger studies are needed to confirm the results and to investigate which alterations are condition-specific and which are common across chronic pain conditions. The presence of inflammation could promote the spreading of pain, a hallmark sign of CWP. As it has been suggested that prevalent comorbidities to pain (e.g., depression and anxiety, poor sleep, and tiredness) also are associated with inflammation, it will be important to determine whether inflammation may be a common mediator.

  • 19.
    Gordh, T
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Sharma, H S
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Chronic spinal nerve ligation induces microvascular permeability disturbances, astrocytic reaction, and structural changes in the rat spinal cord.2006Ingår i: Acta Neurochir Suppl, ISSN 0065-1419, Vol. 96, s. 335-40Artikel i tidskrift (Refereegranskat)
  • 20.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala Univ Hosp, Ctr Pain Management & Res, S-75185 Uppsala, Sweden..
    A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord2017Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 15, s. 79-80Artikel i tidskrift (Övrigt vetenskapligt)
  • 21.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Analysis of C-reactive protein (CRP) levels in pain patients - Can biomarker studies lead to better understanding of the pathophysiology of pain?2016Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 11, s. 165-166Artikel i tidskrift (Övrigt vetenskapligt)
  • 22.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Commentary on: Lidocaine for spinal anesthesia. A study of the concentration in the spinal fluid2007Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 51, nr 8, s. 1016-1017Artikel i tidskrift (Refereegranskat)
  • 23.
    Gordh, Torsten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Chu, Haichen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Spinal nerve lesion alters blood-spinal cord barrier function and activates astrocytes in the rat2006Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 124, nr 1-2, s. 211-221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alterations in the spinal cord microenvironment in a neuropathic pain model in rats comprising right L-4 spinal nerve lesion were examined following 1, 2, 4 and 10 weeks using albumin and glial fibrillary acidic protein (GFAP) immunoreactivity. Rats subjected to nerve lesion showed pronounced activation of GFAP indicating astrocyte activation, and exhibited marked leakage of albumin, suggesting defects of the blood-spinal cord barrier (BSCB) function in the corresponding spinal cord segment. The intensities of these changes were most prominent in the gray matter of the lesioned side compared to them contralateral cord in both the dorsal and ventral horns. The most marked changes in albumin and GFAP inummoreaction were seen after 2 weeks and persisted with mild intensities even after 10 weeks. Distortion of nerve cells, loss of neurons and general sponginess were evident in the gray matter of the spinal cord corresponding to the lesion side. These nerve cell and glial cell changes are mainly evident in the areas showing leakage of endogenous albumin in the spinal cord. These novel observations indicate that chronic nerve lesion has the capacity to induce a selective increase in local BSCB permeability that could be instrumental in nerve cell and glial cell activation. These findings may be relevant to our current understanding on the pathophysiology of neuropathic pain.

  • 24.
    Gordh, Torsten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Karlsten, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    [In Process Citation].2015Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112Artikel i tidskrift (Refereegranskat)
  • 25.
    Gordh, Torsten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Bodolea, Constatin
    Hewitt, Ellen
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Cathepsin S is increased in cerebrospinal fluid from patients with neuropathic pain: A support of the microglia hypothesis in humans2014Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 5, nr 3, s. 208-209Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: Cathepsin S has been reported to be a biomarker of spinal microglial activation, a process suggested to be involved in the pathophysiology of chronic neuropathic pain. So far this has been shown only in animal experiments. The aim of this study was to investigate the concentrations of cathepsin S in human cerebrospinal fluid (CSF) samples from a well-defined patient cohort suffering from neuropathic pain as compared to controls.

    Methods: CSF samples from patients suffering from chronic neuropathic pain (n = 14) were analyzed for cathepsin S levels using commercial sandwich ELISAs (DY1183, R&D Systems, Minneapolis, MN, USA). Control CSF was sampled from patients undergoing minor urological surgical procedures under spinal anaesthesia (n = 70), having no obvious pain suffering.

    Results: The neuropathic pain group had significantly higher levels of CSF cathepsin S (median 15189 pg/mL, range 3213–40,040), than the control group (median 5911 pg/mL, range 1909–17,188) (p < 0.005, Mann–Whitney U-test).

    Conclusion: The results support the existence of microglial activation in chronic neuropathic pain patients. CSF Cathepsin S may serve as a potential biomarker for this specific mechanism linked to neuropathic pain. In the future, Cathepsin S inhibiting drugs might become a new treatment alternative for neurophatic pain.

  • 26. Hamunen, Katri
    et al.
    Laitinen-Parkkonen, Pirjo
    Paakkari, Pirkko
    Breivik, Harald
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Jensen, Niels Henrik
    Kalso, Eija
    What do different databases tell about the use of opioids in seven European countries in 2002?2008Ingår i: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 12, nr 6, s. 705-715Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective

    The objective of this paper was to analyse opioid consumption in a number European countries using different sources of data.

    Methods

    Data were extracted from the United Nations’ International Narcotics Control Board Report (INCB) 2003 and from the registers of the national health authorities in seven countries where data were available for 2002. The amount of opioid used was calculated as daily defined doses per 1000 inhabitants per day (DDD/1000/day). Danish Register of Medicinal Products Statistics was further explored for characteristics of opioid consumption (age, gender, type of opioids consumed) by patients in primary care. Total opioid consumption and consumption of 11 selected opioids (7 strong and 4 weak) were analysed. The amount of opioids consumed by outpatients was also examined.

    Results

    There were considerable differences in the number of opioids reported and significant discrepancies in the amounts of opioids consumed between the national data and the INCB report. The source of data for the national registers on drug consumption varied (pharmacies or wholesale). The INCB data provide information on opioid import and estimated need rather than on medical consumption.

    Conclusions

    Caution is required when interpreting the data on opioid consumption between countries because of differences in the collection and reporting of data. Better recording of opioid consumption is needed for meaningful analysis of opioid consumption and its possible effect on pain management in different countries. Data on opioids consumed for cancer-related pain in comparison with chronic non-malignant pain are needed. A uniform method of collection of data on analgesic consumption should be established for all European countries.

  • 27.
    Hysing, Eva-Britt
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Smith, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Eriksson, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Karlsten, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Butler, Stephen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Identifying characteristics of the most severely impaired chronic pain patients treated at a specialized inpatient pain clinic2017Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, nr 1, s. 178-185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and aims: Patients suffering from chronic nonmalignant pain constitute a heterogeneous population in terms of clinical presentation and treatment results. Few data are available about what distinguishes different groups in this huge population of patients with chronic persistent pain (CPP). A subgroup that is poorly studied, consists of the most severely impaired chronic pain patients. At the Uppsala University Hospital Pain Clinic, there is a specialized department accepting the most complex patients for rehabilitation. In the endeavour to improve and evaluate treatment for this subgroup, a better understanding of the complex nature of the illness is essential. This prospective study aimed to describe the characteristics of this subgroup of patients with CPP.

    Methods: Seventy-two consecutive patients enrolled in the Uppsala programme were evaluated. We collected data on demographics, type of pain and experienced symptoms other than pain using a checklist of 41 possible symptoms. Psychiatric comorbidity was assessed by a psychiatrist using a structured clinical interview. Quality of life (QoL), pain rating and medication/drug/alcohol usage were measured by validated questionnaires: SF-36, NRS, DUDIT and AUDIT. Concerning physical functioning and sick leave, a comparison was made with data from the Swedish Quality Register Registry for pain rehabilitation (SQRP).

    Results: The cohort consisted of 61% women and the average age was 45 (range 20-70) years. For this cohort, 74% reported being on sick leave or disability-pension. In the SQRP 59% were on sick leave at the time they entered the rehabilitation programmes [1]. On average, the study-population reported 22 symptoms other than pain, to be at a high rate of severity. Patients treated in conventional pain rehabilitation programmes reported a mean of 10 symptoms in average. Symptoms reported with the highest frequency (>80%), were lethargy, tiredness, headache and difficulties concentrating. Seventysix percent were diagnosed with a psychiatric disorder. Sixty-nine fulfilled the criteria for depression or depression/anxiety disorder despite that most (65%) were treated with psychotropic medication. Alcohol/drug abuse was minimal. Seventy-one percent were on opioids but the doses were moderate (<100 mg) MEq. The pain rating was >= 7 (out of a maximum of 10) for 60% of the patients.

    Conclusion: This study describes what makes the subgroup of pain patients most affected by their pain special according to associated factors and comorbidity We found that they were distinguished by a high degree of psychiatric comorbidity, low physical functioning and extreme levels of symptom preoccupation/hypervigilance. Many severe symptoms additional to pain (e.g. depression/anxiety, tiredness, disturbed sleep, lack of concentration, constipation) were reported. The group seems hypervigilant, overwhelmed with a multitude of different symptoms on a high severity level.

    Implications: When treating this complex group, the expressions of the illness can act as obstacles to achieve successful treatment outcomes. The study provides evidence based information, for a better understanding of the needs concerning these pain patients. Our result indicates that parallel assessment and treatment of psychiatric comorbidities and sleep disorders combined with traditional rehabilitation, i.e. physical activation and cognitive reorganization are imperative for improved outcomes.

  • 28.
    Hysing, Eva-Britt
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Smith, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen. Univ Edinburgh, Sch Math, Kings Bldg, Edinburgh EH9 3FD, Midlothian, Scotland;Univ Edinburgh, Maxwell Inst Mathemat Sci, Kings Bldg, Edinburgh EH9 3FD, Midlothian, Scotland.
    Karlsten, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Bothelius, Kristoffer
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program2019Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 19, nr 2, s. 235-244Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and aims: Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP).

    Methods: Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation.

    Results: Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found.

    Conclusions: Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the "sickness-syndrome" and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved.

  • 29.
    Kalliomäki, Maija
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Kieseritzky, Johanna V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Handkirurgi.
    Schmidt, Roland
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Hägglöf, Björn
    Karlsten, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sjögren, Niclas
    Albrecht, Phil
    Gee, Lucy
    Rice, Frank
    Wiig, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Handkirurgi.
    Schmelz, Martin
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Structural and functional differences between neuropathy with and without pain?2011Ingår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 231, nr 2, s. 199-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aimed to find functional and structural differences in neuropathy between patients with and without chronic pain following nerve injury. We included 30 patients requiring hand surgery after a trauma, with 21 reporting chronic pain for more than one year after the injury, while 9 did not suffer from injury-related chronic pain. We assessed mechanical sensitivity, thermal thresholds, electrically induced pain and axon reflex erythema and cutaneous nerve fiber density in skin biopsies of the injured site and its contralateral control. Epidermal fiber density of the injured site was reduced similarly in both patient groups. Thresholds for cold and heat pain and axon reflex areas were reduced in the injured site, but did not differ between the patient groups. Only warmth thresholds were better preserved in the pain patients (35.2 vs. 38.4 degrees C). Neuronal CGRP staining did not reveal any difference between pain and non-pain patients. Epidermal innervation density correlated best to warmth detection thresholds and deeper dermal innervation density to the area of the axon reflex erythema. No specific pattern of subjective, functional or structural parameters was detected that would separate the neuropathy patients into pain and non-pain patients. Specific staining of additional targets may help to improve our mechanistic understanding of pain development.

  • 30.
    Kalliomäki, Maija-L
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Meyerson, Josefine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Gunnarsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sandblom, Gabriel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Long-term pain after inguinal hernia repair in a population-based cohort; risk factors and interference with daily activities2008Ingår i: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Eur J Pain, ISSN 1090-3801, Vol. 12, nr 2, s. 214-225Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the Swedish Hernia Register 2834 inguinal hernia repairs in 2583 patients were registered in the county of Uppsala 1998-2004. In May 2005 the 2421 patients still alive were requested by mail to fill in a validated questionnaire concerning postherniorrhaphy pain. The final response rate became 72%. Altogether 519 patients (29%) stated that they had pain in the operated groin to some extent during past week. In 98 patients (6%) the pain interfered with daily activities. Factors associated with an increased risk of residual pain in a multivariate logistic regression analysis were age below median, operation for recurrence, open repair technique, history of preoperative pain, and less than three years from surgery. Factors not associated with occurrence of residual pain were gender, method of anaesthesia during surgery, hernia sac diameter, postoperative complications, hernia type, need for emergency operation, reducibility of the hernia sac and complete dissection of the hernia sac. Factors found to be associated with impairment of function due to pain in a multivariate logistic regression analysis were: age below median, female gender, medial hernia, open repair technique, postoperative complications, need for operation for recurrence, presence of preoperative pain and less than three years from surgery. The possibility of long-term pain as an outcome after hernia operations should be taken into consideration in the decision making prior to operation.

  • 31.
    Kvarnström, Ann
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Karlsten, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Quiding, Hans
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    The analgesic effect of intravenous ketamine and lidocaine on pain after spinal cord injury2004Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 48, nr 4, s. 498-506Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:  Pain following spinal cord injury (SCI) is a therapeutic challenge. Only a few treatments have been assessed in randomized, controlled trials. The primary objective of the present study was to examine the analgesic effect of ketamine and lidocaine in a group of patients with neuropathic pain below the level of spinal cord injury. We also wanted to assess sensory abnormalities to see if this could help us to identify responders and if treatments resulted in changes of sensibility.

    Methods:  Ten patients with spinal cord injury and neuropathic pain below the level of injury were included. The analgesic effect of ketamine 0.4 mg kg−1 and lidocaine 2.5 mg kg−1 was investigated. Saline was used as placebo. The drugs were infused over 40 min. A randomized, double-blind, three-period, three-treatment, cross-over design was used. Systemic plasma concentrations of ketamine and lidocaine were assessed. Pain rating was performed using a visual analogue scale (VAS). Sensory function was assessed with a combination of traditional sensory tests and quantitative measurement of temperature thresholds.

    Results:  Response to treatment, defined as 50% reduction in VAS-score during infusion, was recorded in 5/10 in the ketamine, 1/10 in the lidocaine and 0/10 in the placebo groups. Neither ketamine nor lidocaine changed temperature thresholds or assessments of mechanical; dynamic and static sensibility. Nor could these sensory assessments predict response to treatment in this setting. Lidocaine and particularly ketamine were associated with frequent side-effects.

    Conclusion:  Ketamine but not lidocaine showed a significant analgesic effect in patients with neuropathic pain after spinal cord injury. The pain relief was not associated with altered temperature thresholds or other changes of sensory function.

  • 32.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Carlsson, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The effects of age and gender on plasma levels of 63 cytokines2015Ingår i: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 425, s. 58-61Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytokines play important roles as regulators of cell functions, and over the last decades a number of cytokine assays have been developed. The aim of the present study was to investigate the effects of age and gender on a large number of cytokines. Plasma samples were collected from 33 healthy blood donors. The samples were analyzed using the multiplex proximity extension assay (PEA) allowing simultaneous measurement of 92 cytokines and four technical controls. Biomarkers with less than 80% quantitative results were excluded leaving 63 cytokines that were analyzed for the effects of gender and age. The plasma level of three of the investigated biomarkers (DNER, MCP-4 and MMP-10) were found to be significantly different for the two genders (adjusted p-value <0.05), and 15 of the biomarkers (CCL11, CCL25, CDCP1, CSF-1, CXCL11, CXCL9, FGF-23, Flt3L, HGF, IL-10RB, MCP-3, MCP-4, MMP-10, OPG, VEGF-A) were significantly associated with age. This study reveals the effects of age and gender on a large number of cytokine assays. CXCL5 and TNFB were significantly higher in females, while the other markers with significant gender-dependent differences were higher in males. For the markers that were significantly associated with age, only CXCL6 was found to decrease with age, while the other biomarkers increased with age.

  • 33.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Carlsson, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Bodolea, Constantin
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid2015Ingår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, nr 2, s. 514-518Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.

  • 34.
    Lesniak, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Med Univ Warsaw, Ctr Preclin Res & Technol, Dept Pharmacodynam, Warsaw, Poland.
    Aarnio, Mikko
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Diwakarla, Shanti
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Norberg, Thomas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gordh, T
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.2018Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 194, s. 26-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: D-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for D-deprenyl in synovial membrane explants from arthritic patients.

    Main methods: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [H-3]D-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation.

    Key findings: The [H-3]D-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [H-3]D-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [H-3]D-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [H-3]D-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation.

    Significance: Our study was the first to show the biochemical characteristics of the [H-3]D-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.

  • 35.
    Lesniak, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Aarnio, Mikko
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Jonsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Norberg, Thomas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl2016Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 152, s. 231-237Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: D-deprenyl is a useful positron emission tomography tracer for visualization of inflammatory processes. Studies with [C-11]-D-deprenyl showed robust uptake in peripheral painful sites of patients with rheumatoid arthritis or chronic whiplash injury. The mechanism of preferential D-deprenyl uptake is not yet known, but the existence of a specific binding site was proposed. Thus, in the present study, we sought to identify the binding site for D-deprenyl and verify the hypothesis about the possibility of monoamine oxidase enzymes as major targets for this molecule. Main methods: A high-throughput analysis of D-deprenyl activity towards 165 G-protein coupled receptors and 84 enzyme targets was performed. Additionally, binding studies were used to verify the competition of [H-3]D-deprenyl with ligands specific for targets identified in the high-throughput screen. Key findings: Our high-throughput investigation identified monoamine oxidase-B, monoamine oxidase-A and angiotensin converting enzyme as potential targets for D-deprenyl. Further competitive [3H] D-deprenyl binding studies with specific inhibitors identified monoamine oxidase-B as the major binding site. No evident high-affinity hits were identified among G-protein coupled receptors. Significance: Our study was the first to utilize a high-throughput screening approach to identify putative D-deprenyl targets. It verified 249 candidate proteins and confirmed the role of monoamine oxidase - B in D-deprenyl binding. Our results add knowledge about the possible mechanism of D-deprenyl binding, which might aid in explaining the increased uptake of this compound in peripheral inflammation. Monoamine oxidase-B will be further investigated in future studies utilizing human inflamed synovium.

  • 36.
    Lind, Anne-Li
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Yu, Di
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Freyhult, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Bodolea, Constantin
    Department of Anaesthesia and Intensive Care, University of Medicine and Pharmacy, Cluj, Napoca, Romania..
    Ekegren, Titti
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Gustafsson, Mats G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Katila, Lenka
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 2, artikel-id e0149821Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 μL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest.

  • 37.
    Linnman, Clas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Appel, Lieuwe
    The PET Center in Uppsala, Sweden.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Söderlund, Anne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engler, Henry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Elevated [11C]D--Deprenyl Uptake in Chronic Whiplash Associated Disorder Suggests Persistent Musculoskeletal Inflammation2011Ingår i: PLoS ONE, ISSN 1932-6203, Vol. 6, nr 4, s. e19182-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer C-11 D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that C-11 D-deprenyl is a promising tracer for these purposes.

  • 38.
    Miclescu, Adriana A
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Svahn, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Evaluation of the protein biomarkers and the analgesic response to systemic methylene blue in patients with refractory neuropathic pain: a double-blind, controlled study2015Ingår i: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 8, s. 387-397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM: This study was carried out in patients with neuropathic pain in order to assess the analgesic effects and changes in protein biomarkers after the administration of methylene blue (MB), a diaminophenothiazine with antioxidant and anti-inflammatory properties, and with inhibitory effects on nitric oxide.

    MATERIALS AND METHODS: Ten patients with chronic refractory neuropathic pain were randomized to receive either MB (10 mg/mL Methylthioninium chloride) 2 mg/kg (MB group) or MB 0.02 mg/kg (control group) infused over 60 minutes. Sensory function and pain (Numerical Rating Scale) were evaluated at baseline and at 60 minutes after the start of the infusion. The patients kept a pain diary during the next 24 hours and for the following 4 days. Plasma and urinary concentrations of 8-isoprostane-prostaglandin F2α (8-iso-PGF2α) and plasma protein biomarkers prior to and after the infusions were measured with radioimmunoassay and with proximity extension assay.

    RESULTS: A decrease of the Numerical Rating Scale at 60 minutes in comparison with baseline was observed in the MB (P=0.047) group. The decrease was significant between the MB and the control group on the day of and day after MB infusion (P=0.04 and P=0.008, respectively). There was no difference in systemic protein expressions between groups except for prolactin (PRL) (P=0.02). Three patients demonstrated diminished dynamic mechanical allodynia.

    CONCLUSION: MB decreased the pain levels in patients with chronic therapy-resistant neuropathic pain on the first 2 days after administration. Known as an endocrine modulator on the anterior pituitary gland, MB infusion produced a decrease of PRL. The detailed role of PRL effects in chronic neuropathic pain remains undetermined.

  • 39.
    Miclescu, Adriana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nordquist, Lena
    Uppsala universitet.
    Hysing, Eva-Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Butler, Stephen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Targeting oxidative injury and citokines activity in the treatment with anti-TNF alpha antibodies against CRPS 12013Ingår i: Pain Practice, ISSN 1530-7085, E-ISSN 1533-2500, Vol. 13, nr 8, s. 641-648Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F2-isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.

  • 40.
    Miclescu, Adriana
    et al.
    Multidisciplinary Pain Center, Uppsala University Hospital, Sweden.
    Schmelz, Martin
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Differential analgesic effects of local lidocaine on spontaneous and evoked pain in neuropathic pain: A double blind, randomized controlled study2015Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 8, s. 37-44Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Both peripheral nerve injury and neuroma pain are the result of changes in sodium channel expression. Lidocaine selectively inhibits the spontaneous ectopic activity by binding to sodium channels. Subanesthetics concentrations of lidocaine are able to produce a differential block of the ectopic discharges, but not propagation of impulses, suppressing differentially the associated neuropathic pain symptoms. The aim of this study was to investigate the differences between the analgesic effects of lidocaine 0.5% and a control group of lidocaine 0.1% on several neuroma related pain modalities.

    Methods

    Sixteen patients with neuropathic pain due to painful neuromas caused by nerve injury participated in this randomized, double-blind experiment. The patterns of sensory changes were compared before and after injection of 1 ml lidocaine 0.5% and 0.1% close to the neuroma, the sessions being 1–2 weeks apart. Spontaneous and evoked pains were assessed using a visual analogue scale (VAS), quantitative and qualitative sensory testing. The primary end-point measure was defined as the change in pain score measured from baseline until 60 min after injection. Assessments of spontaneous pain and evoked pain were done post injection at 15 s, 30 s, 1 min, and at 5-min intervals for the first 30-min post injection and then every 10-min to 1 hr post injection. The assessments of pain were performed between the limbs in the following order: spontaneous pain, then assessment of dynamic mechanical allodynia and then hyperalgesia.

    Results

    Lidocaine dose-dependently reduced spontaneous and evoked pain scores by more than 80% with maximum effects between 1 and 5 min for evoked pain and between 3 and 15 min for spontaneous pain. While evoked pain normalized rapidly reaching about 50% of the control level 20 min after the injection, spontaneous pain levels continue to be lower in comparison with baseline values for more than 60 min. When comparing the time course of analgesia between spontaneous and evoked pain, lidocaine-induced a greater reduction of evoked pain, but with shorter duration than spontaneous pain. The differences between evoked pain and spontaneous pain were statistically significant in both groups (lidocaine 0.5% group; p = 0.02 and lidocaine 0.1% group; p = 0.01). Reproducibility was high for all assessed variables. Surprisingly, both lidocaine concentrations produced a sensory loss within the area with hyperalgesia and allodynia: hypoesthesia occurred earlier and lasted longer with lidocaine 0.5% (between 30 s and 5 min) in comparison with lidocaine 0.1% (p = 0.018).

    Conclusion

    Differential analgesic effects of subanesthetic concentrations of local lidocaine on evoked and spontaneous pain in human neuroma suggest that different mechanisms underlie these two key clinical symptoms. Spontaneous pain and evoked pain need an ongoing peripheral drive and any possible CNS amplification change is temporally closely related to this peripheral input.

    Implications

    Painful neuroma represents a clinical model of peripheral neuropathic pain that could lead to a significant step forward in the understanding of pain pathophysiology providing the opportunity to study spontaneous and evoked pain and the underlying mechanisms of neuropathic pain. The proposed model of neuropathic pain allows testing new substances by administration of analgesics directly where the pain is generated.

  • 41.
    Miclescu, Adriana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Svahn, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nitric Oxide Inhibition by Methylene Blue in the Treatment of Neuropathic Pain: A preliminary report2012Konferensbidrag (Refereegranskat)
    Abstract [en]

    Methylene blue (MB) is a diaminophenothiazine with potent antioxidant properties and with inhibitory effects on both nitric oxide synthases and on the enzyme guanylate cyclase. It was recently demonstrated that MB reduces chronic discogenic low back pain, pain after lateral sphincterotomy as well as pain on injection of propofol. The underlying mechanisms of MB treatment in the above clinical pain conditions are not completely understood. Given that NMDA receptor is implicated in hyperalgesia and many of the NMDA effects are mediated through the production of nitric oxide we hypothesized that administration of a nitric oxide antagonist would decrease the pain scores and hyperalgesia in neuropathic pain.

    The aims of the study

    We performed a prospective clinical trial consisting of a double-blinded, crossed-over, randomized clinical trial (RCT). The aim is to determine the clinical effectiveness of methylene blue in the treatment of neuropathic pain.

    Material and methods

    Patients with peripheral or central neuropathic pain were randomized to receive one of two treatments: Methylene blue 2mg/kg (10 mg/mL Methyltioninklorid, Apoteket, Umeå, Sweden) or methylene blue 0.02 mg/kg both infused i.v. over 60 minutes. The pain was measured at baseline and at 60 min after the start of infusion (NRS scale) and also on a diary in the next 24 hours. ECG, pulse, blood pressure, were continuously recorded. Plasma concentrations of 8-isoprostane-prostaglandin F2α (8-iso-PGF2α) an indicator of oxidative injury, were measured according to a highly specific and validated radioimmunoassay (RIA) method at our laboratory. The detection limit for 8-iso-PGF2α is 23 pmol/L (normal values under 80 pmol/L). Cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A) and nNOS were detected in plasma by antibody-based proximity ligation before and after the infusion of MB and placebo. Proximity ligation assay has been used to develop homogeneous immunoassays to detect cytokines in the sub-pg/mL range.

    Statistics Assuming that MB treatment would reduce the NRS 25%, power analysis with

    a = 0.05, b = 0.8, showed that we would need to study 10 patients in each group. The computer program GraphPad was used for all data analyses. Parametric data were analysed by two-way ANOVA. Unpaired Student t-tests, Chi-squared tests and Fisher’s exact probability tests were used as appropriate for comparison between groups. All values are expressed as mean (SD). Statistical significance was accepted at p < 0.05.

    Results

    The mean age of the patients was 65.4±14, mean duration of pain 4.6±2.6. A decrease of VAS at 60 min in comparison with baseline was observed in MB (p=0.047) group, at 6 hours after baseline (p=0.01), 10, 14, 18 h. Differences between MB and placebo were observed on the day of the infusion (p=0.04), day 2 (p=0.008). Adverse reactions

    Conclusions

    A statistically significant in the changes of the VAS scores was obtained in the patients with neuropathic pain after the treatment at 60 min and at 10, 14, 18 hours in the MB group. The study suggests that the infusion of MB may be an alternative for the treatment of neuropathic pain. MB has been in use as a medicinal continuously throughout the past century and it may now return to play an important therapeutic role.

  • 42.
    Miclescu, Adriana
    et al.
    Multidisciplinary Pain Clinic, Uppsala University Hospital, Sweden.
    Svanh, Martin
    Multidisciplinary Pain Clinic, Uppsala University Hospital, Sweden.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Evaluation of the protein biomarkers and the analgesic response to systemic methylene blue in patients with refractory neuropathic pain: a double blind, controlled study2015Ingår i: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 8, s. 387-397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim:

    This study was carried out in patients with neuropathic pain in order to assess the analgesic effects and changes in protein biomarkers after the administration of methylene blue (MB), a diaminophenothiazine with antioxidant and anti-inflammatory properties, and with inhibitory effects on nitric oxide.

    Materials and methods:

    Ten patients with chronic refractory neuropathic pain were randomized to receive either MB (10 mg/mL Methylthioninium chloride) 2 mg/kg (MB group) or MB 0.02 mg/kg (control group) infused over 60 minutes. Sensory function and pain (Numerical Rating Scale) were evaluated at baseline and at 60 minutes after the start of the infusion. The patients kept a pain diary during the next 24 hours and for the following 4 days. Plasma and urinary concentrations of 8-isoprostane-prostaglandin F2α (8-iso-PGF2α) and plasma protein biomarkers prior to and after the infusions were measured with radioimmunoassay and with proximity extension assay.

    Results:

    A decrease of the Numerical Rating Scale at 60 minutes in comparison with baseline was observed in the MB (P=0.047) group. The decrease was significant between the MB and the control group on the day of and day after MB infusion (P=0.04 and P=0.008, respectively). There was no difference in systemic protein expressions between groups except for prolactin (PRL) (P=0.02). Three patients demonstrated diminished dynamic mechanical allodynia.

    Conclusion:

    MB decreased the pain levels in patients with chronic therapy-resistant neuropathic pain on the first 2 days after administration. Known as an endocrine modulator on the anterior pituitary gland, MB infusion produced a decrease of PRL. The detailed role of PRL effects in chronic neuropathic pain remains undetermined.

  • 43.
    Miclescu, Adriana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Walan, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten.
    Essemark, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten.
    Karlsten, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Persistent neuropathic pain after nerve suture surgery2016Ingår i: 16Th World Congress of  Pain IASP26-29 Th September Yokohama, Japan, 2016Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    Aim of Investigation: Iatrogenic nerve injury has been proposed as the main factor responsable for long term-postsurgical pain. The prevalence of chronic neuropathic pain after a known somatosensory lesion in the upper extremity nerves followed by suture surgery was determined.

    Methods:The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale questionnaires were sent out in January 2016 to 1078 patients who underwent nerve repairs operations after traumatic or surgical nerve injuries of the upper limbs between 2006 to 2014 at the Hand Surgery Clinic.

    Results: Three hundred eighty-two patients returned the questionnaire (response rate 35%). Post trauma or post-surgical pain was present in 186 patients (48 %) from those 382 patients who responded to the questionnaire. A total of 87 patients (47 %) of these 186 patients developed chronic pain after the operation. The most common symptom experienced by the patients was the enhanced sensitivity to cold in 69 % of the patients that led to pain and discomfort at temperatures that normally were perceived as being innocuously cool. Other symptoms were diminished sensitivity to stimulation in 55% of the patients and allodynia to light pressure, cold presented in 50% of the patients. The majority of the patients with pain resulting from traumatic or surgical nerve injury (77% of the patients) had no medication for pain, despite the presence of pain more than 50 VAS.

    Conclusions: Persistent neuropathic pain occured in 48% of the patients following nerve suture surgery. Cold intolerance has a high prevalence both in the group of patients with pain and in the group without pain.

  • 44.
    Moen, Aurora
    et al.
    Natl Inst Occupat Hlth, N-0033 Oslo, Norway.;Oslo Univ Hosp, Dept Phys Med & Rehabil, N-0424 Oslo, Norway..
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Roe, Cecilie
    Oslo Univ Hosp, Dept Phys Med & Rehabil, N-0424 Oslo, Norway.;Univ Oslo, Fac Med, N-0316 Oslo, Norway..
    Gjerstad, Johannes
    Natl Inst Occupat Hlth, N-0033 Oslo, Norway.;Oslo Univ Hosp, Dept Phys Med & Rehabil, N-0424 Oslo, Norway.;Univ Oslo, Dept Mol Biosci, N-0371 Oslo, Norway..
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation2016Ingår i: INTERNATIONAL JOURNAL OF INFLAMMATION, ISSN 2090-8040, artikel-id UNSP 3874964Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Earlier studies suggest that lumbar radicular pain following disc herniation may be associated with a local or systemic inflammatory process. In the present study, we investigated the serum inflammatory protein profile of such patients. All 45 patients were recruited from Oslo University Hospital, Ulleval, Norway, during the period 2007-2009. The new multiplex proximity extension assay (PEA) technology was used to analyze the levels of 92 proteins. Interestingly, the present data showed that patients with radicular pain 12 months after disc herniation may be different from other patients with regard to many measurable serum cytokines. Given a false discovery rate (FDR) of 0.10 and 0.05, we identified 41 and 13 proteins, respectively, which were significantly upregulated in the patients with severe pain one year after disc herniation. On the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 (CXCM5; 217% increase), epidermal growth factor (EGF; 142% increase), and monocyte chemotactic protein 4 (MCP-4; 70% increase). Moreover, a clear overall difference in the serum cytokine profile between the chronic and the recovered patients was demonstrated. Thus, the present results may be important for future protein serum profiling of lumbar radicular pain patients with regard to prognosis and choice of treatment. We conclude that serum proteins may be measurable molecular markers of persistent pain after disc herniation.

  • 45.
    Ndjole, Annaby Moussa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Bodolea, Constantin
    Nilsen, Tom
    Gentian AS, Moss, Norway.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Determination of cerebrospinal fluid cystatin C on Architect ci82002010Ingår i: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 360, nr 1-2, s. 84-88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Human cystatin C is a cysteine protease inhibitor produced by all nucleated cells in the body and the protein is present in all body fluids. The concentration in cerebrospinal fluid (CSF) is considerably higher than in plasma. Cystatin C levels seem to influence the development of Alzheimer disease (AD) and low levels in the brain are associated with an increased risk for AD. The aim of this study was to develop a high throughput assay for the quantification of cystatin C in CSF. METHODS: Antigen excess, imprecision, interference, linearity, recovery, sample stability and reference values were evaluated on Architect ci8200 (Abbott Laboratories, Abbott Park, IL, USA). RESULTS: The assay had an antigen-excess limit at 23 mg/L and was linear over the range of 0.84 to 8.33 mg/L. Results > 8.33 mg/L were automatically rerun in a higher dilution. Within-run coefficient of variation (CV) was 1.71, 1.10 and 0.79%, between day CV was 1.71, 0.39 and 1.45%, between-run CV was 0.58, 0.66 and 0.48%, and total CV was 2.49, 1.34 and 1.72% at cystatin C concentrations of 1.39, 3.17 and 6.28 mg/L, respectively. The recovery was 97-102%. No interference at a 7.5% deviation level was observed for 8.5 g/L of hemoglobin or 800 mg/L (1368 micromol/L) of bilirubin. Reference values for cystatin C in cerebrospinal fluid obtained with this method were 2.42-14.33 mg/L.

  • 46.
    Nilsson, Elin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Bodolea, Constantin
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Cerebrospinal fluid cathepsin B and S2013Ingår i: Neurological Sciences, ISSN 1590-1874, E-ISSN 1590-3478, Vol. 34, nr 4, s. 445-448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cathepsins are increased in the brain of elderly animals. We investigate the presence of cathepsin B and S in human cerebrospinal fluid (CSF) plasma and the associations with cystatin C, age and sex. We measured cathepsin B and S concentrations in CSFs from 118 persons, undergoing elective surgical procedures, with ELISA. Both cathepsin B and cathepsin S were positively correlated with age. No correlation was observed between cathepsin B or S and length, height or body mass index. Both cathepsin B and S were positively correlated to the cystatin C concentration in CSF. Calculated reference intervals were 4,893–17,636 pg/mL for cathepsin B and 2,681–11,459 pg/mL for cathepsin S. Elderly individuals had significantly higher levels of both cathepsin B (r s = 0.38, p = 0.00002) and cathepsin S (r s = 0.35, p = 0.0001) in CSF.

  • 47.
    Peterson, Magnus
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Svärdsudd, Kurt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Engler, Henry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Aarnio, Mikko
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Langström, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    PET-Scan Shows Peripherally Increased Neurokinin 1 Receptor Availability in Chronic Tennis Elbow: Visualizing Neurogenic Inflammation?2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 10, s. e75859-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In response to pain, neurokinin 1 (NK1) receptor availability is altered in the central nervous system. The NK1 receptor and its primary agonist, substance P, also play a crucial role in peripheral tissue in response to pain, as part of neurogenic inflammation. However, little is known about alterations in NK1 receptor availability in peripheral tissue in chronic pain conditions and very few studies have been performed on human beings. Ten subjects with chronic tennis elbow were therefore examined by positron emission tomography (PET) with the NK1 specific radioligand [C-11]GR205171 before and after treatment with graded exercise. The radioligand signal intensity was higher in the affected arm as compared with the unaffected arm, measured as differences between the arms in volume of voxels and signal intensity of this volume above a reference threshold set as 2.5 SD above mean signal intensity of the unaffected arm before treatment. In the eight subjects examined after treatment, pain ratings decreased in all subjects but signal intensity decreased in five and increased in three. In conclusion, NK1 receptors may be activated, or up-regulated in the peripheral, painful tissue of a chronic pain condition. This up-regulation does, however, have moderate correlation to pain ratings. The increased NK1 receptor availability is interpreted as part of ongoing neurogenic inflammation and may have correlation to the pathogenesis of chronic tennis elbow.

  • 48.
    Philippot, Gaetan
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Hallgren, Stefan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Fredriksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)2018Ingår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 166, nr 1, s. 203-212Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acetaminophen (AAP; also known as paracetamol) is the most used and only recommended analgesic and antipyretic among pregnant women and young children. However, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and adverse neurobehavioral effects later in life. We hypothesized that the cannabinoid receptor type 1 (CB1R) may be involved in the developmental neurotoxicity of AAP, owing to its interaction with the endocannabinoid system. Here we test if CB1R agonist WIN 55 212-2 (WIN) and AAP can interact when exposure occurs during a neurodevelopmental stage known for increased growth rate and for its vulnerability to AAP exposure. We exposed male NMRI mice on postnatal day 10 to different combinations of AAP and WIN. Adult mice, neonatally co-exposed to AAP and WIN, displayed a significant lack of habituation in the spontaneous behavior test, when compared with controls and single agent exposed mice. These adult adverse effects may at least in part be explained by a reduction of transcript levels of hippocampal synaptophysin (Syp) and tropomyosin receptor kinase B (Trkb), and cerebral cortical fatty acid amide hydroxylase (Faah), 24h after exposure. These findings are consistent with our hypothesis that AAP and WIN can interact when exposure occurs during early postnatal brain development in mice. Assuming our results are relevant for humans, they raise concerns on AAP safety because it is the only recommended analgesic and antipyretic during pregnancy and early life.

  • 49.
    Philippot, Gaëtan
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Fredriksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period2017Ingår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 37, nr 10, s. 1174-1181Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg – 1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice

  • 50.
    Pontén, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Fredriksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Ekotoxikologi.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Ekotoxikologi.
    Neonatal exposure to propofol affects BDNF but not CaMKII, GAP-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain2011Ingår i: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 223, nr 1, s. 75-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Animal studies have shown that neonatal anaesthesia is associated with acute signs of neurodegeneration and later behavioural changes in adult animals. The anaesthetic effect of propofol is thought to be mediated by gamma-amino butyric acid (GABA)(A) receptors. The present study investigated the effects on proteins important for normal neonatal brain development (i.e. BDNF, CaMKII, GAP-43, synaptophysin and tau), and adult spontaneous motor and anxiety-like behaviours in response to diazepam, after neonatal exposure to propofol. Ten-day-old mice were exposed to 0, 10 or 60 mg/kg bodyweight propofol. Neonatal propofol exposure changed the levels of BDNF in the brain, 24h after exposure, but did not alter any of the other proteins. Neonatal propofol exposure significantly changed the adult response to the GABA-mimetic drug diazepam, manifest as no change in spontaneous motor activity and/or reduced sedative effect and an extinguished effect on the reduction of anxiety-like behaviours in an elevated plus maze. Although no adult spontaneous behavioural changes were detected after neonatal propofol exposure, the exposure caused an adult dose-dependent decrease in the response to the GABA-mimetic drug diazepam. These changes may be due to neonatal alterations in BDNF levels.

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